Alzheimer's Disease (AD) is a disease that is difficult to treat and that requires an early diagnosis to control or reduce its effects. AD is a high impact disease in the public health system and one of the most important dementias. Furthermore, it is the fourth largest cause of death worldwide after cardiovascular disorders. AD's prevalence worldwide in those over 65 years of age reaches 12%. Approximately 100,000 persons die per year from AD and its cost to the US economy is US$170 million each year (Wimo and Winblad, 2001).
Dementia, a cognitive syndrome characterized by a decrease in cognitive functions, affects an important percentage of this population. Among all the dementias, AD is the most prevalent and with highest incidence. This situation implies a substantial expense for the government, and it has been determined that there has been an increase in the incidence of AD due to the increase in life expectancy. On the other hand, there is a group of related pathologies, the taupathies, which are disorders in which the tau protein, an essential component of the cytoskeleton, aggregates in the brain to form structures called neurofibrillary tangles (NFTs) (Maccioni and Cambiazo, 1995; Maccioni et al., 2001). NFTs are formed by polymeric tau aggregates, a protein that has been investigated in depth for more than 30 years in the context of Alzheimer's Disease (Maccioni et al., 1986; 1995; 2001). These pathologies have no cure to date, but finding a diagnostic procedure for their early detection would allow substantial patient survival and quality of life. Additionally, a procedure and technologies allowing an accurate diagnosis of AD would stimulate the development of therapies to control the disease.
The fast development of neuroimaging and radiopharmaceutical technologies has made important contributions to the understanding of the pathophysiological processes occurring in the human brain possible. However, such approximations in many neurodegenerative disorders, such as AD, are still very non-specific and therefore do not allow accurate diagnosis.
The publications of Klunk et al., (2004), Verhoeff et al. (2004), Glodzik et al. (2005), and Mosconi et al. (2005, 2007), have shed light on some senile plaque markers. However, notwithstanding having been developed some years ago, their clinical application has not been established or implemented. The development of radioligands to obtain in vivo images of Aβ plaques and neurofibrillary tangles (NFTs), whether by PET, SPECT or other technologies, is currently an important and active area of Nuclear Medicine. The design and biological evaluation of agents to obtain Aβ plaque images, whether by PET or SPECT, requires knowledge of the functional-structural relations of these radioligands, which vary from large proteins and peptides such as Aβ and radioactive monoclonal antibodies down to small molecules derived from Congo red, Chrysamine-G, Thioflavin-T, and Acridine Orange. Recent studies have shown that with this type of technology it is possible to obtain in vivo images in humans suggesting both senile plaques and NTFs, although the correlation has not been established. The most useful radiotracers to this date have been relatively small molecules (<600 Da). The development of radioligands to obtain in vivo plaque images of Aβ-amyloid (PAB) and NFTs, whether by PET or SPECT, has been an important and active area in the radiopharmaceutical industry (Mathis et al., 2005). The marking of specific pathological abnormalities will be of great use in the early diagnosis and identification of persons at risk of developing a given disease.
The only compounds that have been tested in humans to detect abnormal structures in the brains of AD patients are the Pittsburg compound (PIB) and FDDNP, which mark senile amyloid plaques. Amyloids, however, are not a pathognomonic sign in the detection of Alzheimer (Maccioni et al., 2001), and its marking lacks specific pathological diagnostic value. PIB is a compound derived from thioflavine T that binds to senile plaques in the brain, composed primarily of amyloid peptides. PIB has been used without success as a diagnostic tool to detect the accumulation of senile plaques in the brains of patients with AD and other dementias. Although PIB can generate images that suggest the layout of senile plaques visualized by means of positron emissions (PET technology), it has practically had no use for AD diagnosis. This is because senile plaques are not pathognomonic of Alzheimer's Disease, i.e., there are healthy individuals with an important amount of senile plaques in their brains that evidence no cognitive deterioration whatsoever. No compound specifically marking NFT lesions formed by tau aggregates has therefore been tested, so that the molecules of this invention are the only products actually able to specifically mark these structures.
To this date, different types of neuroimaging techniques have been tested without positive results as an approximation to the diagnosis and assessment of the evolution of AD and taupathies in time (Mathis et al., 2005, Rusinek et al., 2003, Stoub et al., 2005, Rosen et al., 2005, Godbolt et al., 2006). These techniques include: Computerized Axial Tomography, Nuclear Magnetic Resonance (NMR), both structural (sNMR) and functional (fNMR), Single Photon Emission Tomography (SPECT), and Positron Emission Tomography (PET). This last technique provides information on the glucose brain metabolism. All these neuroimaging techniques have the advantage of being technically non-invasive so that they may be applied on repeated occasions and at distinctive time intervals in order to assess and identify brain anomalies before patients present the full clinical picture (Rusinek et al., 2003). In short, standard diagnostic procedures by means of neuroimagery are not specific to AD, since virtually all efforts to achieve an AD neuroimaging technology have been addressed at amyloid deposits, including the “Pittsburgh compound” (PIB) and the 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile (FDDNP) (Klunk et al., 2004, Mosconi et al., 2007, Small et al., 2007); these detect amyloids as well as NFTs, and therefore do not allow selective visualization. It is not clear from these studies what lesions they intend to visualize (for example ‘diffuse’ vs. ‘complete’ plaques, etc.). It is known that the first compound does not visualize NFTs, and the latter can visualize different types of lesions, besides NFTs, so that it is not useful as a diagnostic tool (Mathis et al., 2005, Furomoto, 2007). On the other hand, patent applications PCT/US96/05918; PCT/US98/07889; PCT/JP01/02204 and PCT/JP01/02205 describe compounds that are unable to selectively identify NTFs.
The development of pathology-specific radiomarkers for neurodegenerative disorders is essential not only for the diagnosis but also to monitor new AD therapies. It should be noted that a confirming AD diagnosis can only be made through neuropathological means after a “postmortem” analysis of cerebral tissues. However, there is a possibility of obtaining images of the neurofibrillary tangles (NFTs), the primary histological-molecular sign of AD and taupathies. A powerful tool would thereby be available for definitive in vivo neuropathological diagnosis as well as a method to assess the evolution of AD pathophysiological processes (Lavados et al., 2005, Fernández et al., 2008, Kuljis, 2008). There are some approximations to this need, but until now a fully satisfactory and specific diagnosis tool has not been developed. This has kept the problem of diagnosing AD at an early stage as still be resolved (US2006018825; WO02069965; Okamura, 2004 and 2005). Okamura, for example, has described a set of compounds derived from benzimidazoles to detect Aβ amyloid peptide aggregates, without delving in the study of the use of these benzimidazoles as radiotracers in PET diagnosis by means of the detection of neurofibrillary tangles. However, none of the compounds analyzed by Okamura's group have been used in clinical practice, nor has there been any success in their use in PET imaging, and their preclinical studies could take some time to validate their possible use. They are therefore far from being considered as potential radiotracers to identify NFTs by means of Positron Emission Tomography (PET). In this context, our invention is addressed at compounds that bind with high specificity to tau aggregates and that can be used as pathology-specific radiotracers in the early diagnosis of Alzheimer's Disease.
The possibility of obtaining images of AD neurofibrillary tangles, or of any other pathognomonic proteins will provide medicine with the unprecedented opportunity of a definitive diagnosis that can today only be obtained by means of postmortem neuropathological studies. It would additionally provide the possibility of an early diagnosis, a method to study the evolution of the pathological process and a model to assess specific therapeutic interventions.
A specific neuroimaging diagnosis is therefore required for a given lesion. For this reason, the benzimidazole compounds (BZs) able to bind to aggregate tau in the pathological form present in AD are the most promising radiotracers for the development of PET neuroimaging technology. Even more interesting, the present invention provides known and clinically proven benzimidazoles that bind to tau aggregates. The important benefits derived from this invention are: 1) Specific pathological diagnosis, 2) Early diagnosis and the possibility of a presymptomatic diagnosis of AD, 3) Understanding of the natural evolution of the disease and its pathophysiology, and 4) Ability to directly measure the effects of specific therapies that may be developed in the future. This is because this invention makes it possible to obtain images with 18F-benzimidazoles molecules, thereby proving its differential affinity for tau in neurofibrillary tangles (NFT) and not with normal or monomeric tau, nor with Aβ peptide aggregates, which makes our technology highly specific and reliable for the definite diagnosis of AD. The benzimidazoles in the present invention have the advantage that they are drugs that are already used in medicine for other purposes and that do not have serious secondary effects in patients.